HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer.

Détails

ID Serval
serval:BIB_C54E59BBFAF3
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer.
Périodique
Journal of Clinical Oncology
Auteur(s)
Spraggs C.F., Budde L.R., Briley L.P., Bing N., Cox C.J., King K.S., Whittaker J.C., Mooser V.E., Preston A.J., Stein S.H., Cardon L.R.
ISSN
1527-7755 (Electronic)
ISSN-L
0732-183X
Statut éditorial
Publié
Date de publication
2011
Volume
29
Numéro
6
Pages
667-673
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Résumé
PURPOSE: Hepatobiliary adverse events (AEs) have been observed in a small proportion of patients with metastatic breast cancer (MBC) treated with lapatinib. This study sought to identify gene variants associated with lapatinib-induced ALT elevation and hepatobiliary AEs.¦PATIENTS AND METHODS: A two-stage pharmacogenetic investigation of ALT elevation was conducted in lapatinib-treated patients with MBC. Exploratory marker identification evaluated classical HLA alleles, candidate genes, and genome-wide screening in 37 cases with ALT greater than 3 times the upper limit of normal (ULN) and 286 controls with ALT ≤ 1× ULN, selected from 901 lapatinib-treated patients in 12 trials. Markers achieving prespecified association thresholds were progressed to an independent confirmatory data set of 24 ALT cases and 155 controls selected from a subsequent trial of 374 lapatinib-treated patients.¦RESULTS: Of 58 variants associated with ALT elevation in the exploratory data set, four exceeded the prespecified significance threshold in the confirmatory analysis. These variants reside in the same MHC genomic locus and include HLA-DQA1*02:01. In the confirmatory study, DQA1*02:01 allele carriage was present in 71% of ALT cases and in 21% of controls (P < .001; odds ratio, 9.0; 95% CI, 3.2 to 27.4). As a predictor of liver safety risk in ALT cases versus noncases, DQA1*02:01 had negative and positive predictive values of 0.97 (95% CI, 0.95 to 0.99) and 0.17 (95% CI 0.10 to 0.26), respectively.¦CONCLUSION: These results support a role for immune mechanisms in lapatinib-induced hepatotoxicity. Further work is required to determine whether testing for DQA1*02:01 allele carriage is clinically useful in managing liver safety risk during lapatinib treatment.
Mots-clé
Aged, Alanine Transaminase/blood, Antineoplastic Agents/adverse effects, Breast Neoplasms/drug therapy, Breast Neoplasms/genetics, Case-Control Studies, Female, Genetic Predisposition to Disease/genetics, Genotype, HLA-DQ Antigens/genetics, HLA-DQ alpha-Chains, Humans, Liver/drug effects, Liver Diseases/etiology, Liver Function Tests, Middle Aged, Quinazolines/adverse effects, Randomized Controlled Trials as Topic, Risk Factors
Pubmed
Web of science
Création de la notice
22/03/2012 10:44
Dernière modification de la notice
20/08/2019 16:40
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